Process for making esters of substituted polyhydronaphthalene acids



3,042,707 Patented July 3, 1962 3,042,707 1 PROCESS FOR MAKING ESTERS F SUBSTITUTED POLYHYDRONAPHTHALENE ACIDS Robert Joly, Montmorency, and Julien Warnant, Neuillysur-Seine, France, assignors, by mesne assignments, to

Ronssel-Uclaf, S.A., Paris, France, a corporation of France N0 Drawing. Filed Apr. 30, 1958, Ser. No. 731,871

Claims priority, application France June 14, 1957 1 Claim. (Cl. 260-468) The present invention relates to a substituted polyhydronaphthalene carboxylic acid and its lower alkyl esters and, more particularly, to the levorotatory SIB-acetoxy- 2oz methoxy 7 oxo l,2,3,4,4au7,8,8au octahydronaphalene-lB-carboxylic acid and its lower alkyl esters, and to a process of making same.

Said 3B-acetoxy-Za-methoxy-7 oxo-l,2,3,4,4aa,7,8,8aaoctahydronaphthalene-lfl-carboxylic acid and its ester correspond to the following Formula I OCH;

wherein R represents a member selected from the group consisting of hydrogen and a lower alkyl radical.

These compounds are important intermediates in the synthesis of reserpine, deserpidine, rescinnamine, and related compounds.

In commonly assigned application Serial No. 693,028 filed on October 29, 1957, now US. Patent No. 2,952,682, a process of producing reserpine is described wherein the dextrorotatory 5B-hydroxy-8-oxo-l,4,4au,5,8,8aa-hexahydronaphthalene-lfi-car-boxylic acid is used as starting material and the methyl ester of 3fi-acetoxy-2u-methoxy-7- oxo 1,2,3,4,4aa,7,8,8au octahydronaphthalene 1 3'- carboxylic acid is an important intermediate. Said methyl ester is prepared by esterification of the levorotatory 3;?- hydroxy 20c methoxy 7 oxo l,2,3,4,4au,7,8,8au hydronaphthalene-lfi-carboxylic acid by means of diazomethane and acetylation of the resulting methyl ester.

It is one object of the present invention to provide a simple and economical process suitable for large scale production of the levorotatory 3B-acetoxy-2a-methoxy-7- oxo .1,2,3,4,4aa,7,8,8au octahydronaphthalene 1e carboxylic acid and its lower alkyl esters of the above given Formula 1.

Another object of the present invention is to provide the levorotatory 3,3-acetoxy-2a-methoxyJ-oXo-1,2,3,4, 4au,7,8,8aa-octahydronaphthalene-lfi-carboxylic acid and its lower alkyl esters.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

In principle, the present invention consists in producing the lower alkyl esters of 3,8-hydroxy-2a-methoxy-7- oxo 1,2,3,4,4au,7,8,8,aa octahydronaphthalene 1,3 carboxylic acid by a process more readily applicable to large scale production which process avoids the use of diazomethane as esterifying agent. Diazomethane is not only an expensive and dangerous reagent but also allows only the production of methyl esters.

According to the process of the present invention the levorotatory 3,8-hydroxy-2a-methoxy-7-oxo-1,2,3,4,4au,7, 8,8au-octahydronaphthalene-lfl-carboxylic acid is first acetylated to 3fl-acet0Xy-2a-methoxy-7-oxo-1,2,3,4,4aa,7, 8,8aa-octahydronaphthalene-lp-carboxylic acid. An alkali metal salt of said acid is then prepared and esterified a manner that the reaction mixture never turns alkaline.

amine.

The levorotatory 3B-acetoxy-Zu-methoxy-7-oxo-1,2,3,4, 4aa,7,8,8am octahydronaphthalene 1B carboxylic acid which has not yet been described, is prepared according to the present invention by subjecting the levorotatory 3B hydroxy 20c methoxy 7 oxo 1,2,3,4,4aoz,7,8,83.oz octahydronaphthalene-lfl-carboxylic acid to the action of acetic acid anhydride in the presence of a tertiary base, for instance, pyridine, methyl ethyl pyridine or triethyl- It is surprising and it was not to be foreseen that during this reaction no lactonization takes place. According to the present invention, said method of acetylation is carried out most profitably when the zinc salt of 3fi-hydroxy-Zu-methoxy-7-oxo-1,2,3,4,4aa,7,8,8aa-octahydronaphthalene-lfi-carboxylic acid is acetylated, thus avoiding the isolation of the levorotatory 3B-hydroxy-2amethoxy 7 0x0 1,2,3,4,4aoz,7,8,8floc octahydronaphthalene-lB-carboxylic acid. Said zinc salt is obtained according to the process described in US. Patent Number 2,952,682 on reducing the levorotatory lactone of 6a-bromo-8p-hydroxy-2a-methoxy-3fififi-epoxyJ-oxo- 4au,8aa decahydronaphthalene 1B carboxylic acid by means of zinc in the presence of acetic acid.

The process according to the present invention. is illustrated by the following formulas and equations:

III

Zinc salt of III As stated hereinabove, the starting material for carrying out the process according to the present invention, the

levorotatory 3 ,B-hydroxy-Za-methoxy-7-oxo-1,2,3,4,4aa,7,

8,8a -octahydronaphthalene-1 [S-carboxylic acid of F ormu la III or its zinc salt is obtained by dissolving, for instance, the levorotatory lactone of 6a-bromo-8fl-hydroxy- 2a methoxy- 35,5 3 epoxy 7 oxo 4aa,8a x deca- V hydronaphthalene-lfl-carboxylic acid of Formula II in a mixture of acetone and acetic acid, cooling the solution to about +5 C. and adding zinc powder thereto. The mixture is stirred for some time at a temperature of about 15 C., filtered, and the filtrate is evaporated to dryness in a vacuum. The evaporation residue is dissolved in chloroform containing 20% of ethanol, water is added, the solution is acidified with 7 N sulfuricacid to a pH of 1.0, and is extracted by means of chloroform containing 20% of ethanol. The combined chloroform extracts are dried over magnesium sulfate and evaporated to dryness in ayacuum On recrystallization from a mixture of' acetone and, ether (2:3), substantially pure la III is obtained. p 7 Thelevorotatory lactone of 6oibromo-8fi-hydroxy.-2 an'iethoxy 35,56 epoxy 7 oxo 4au,8aa decahydro- 'naphthalene-lfl-carboxylic acid is obtained by lectonizing the dextrorotatory 5,6-lrydroxy-8-oxo 1,4,4aa,5,8,8a hexahydronaphthalene 15 f carboxylic acid by heating underrefiux in methylene chloride with a mixture of sodium acetate and acetic acid anhydride. The resulting levorotatory lactone of 5/3ehydroxy-8-oxo-1,4,4aa,5,

8,8aa hexahydronaphthalene lfi carboxy-lic acid is carboxylic acid which, on reaction with N-bromo succinimide in dilute sulfuric acid yields the levorotatory 1,8-lactone of 6a-bromo-7fi,8,6-dihydroxy-2a-methoxy-3fl,

V 5/3-epoxy-4aa,8aot decahydronaphthalene 1,8 carboxylic acid. On oxidation by means of chromic acid in acetic acid, the levorotatory lactone of 6m-bromo-8/3-hydroxy-2a-methoxy 3,8,56 epoxy 7 oxo 4aa,8aa-

decahydronaphthalene 1B carboxylic acid of Formula II is obtained which is then converted by reaction with zinc powder in acetone and acetic acid into the levorotatory 3,8 hydroxy 20; methoxy 7 oxo l,2, 3,4,4aa, 7,8,8a'm' octahydronaphthalene 1 3 carboxylic acid of Formula III or its zinc salt, both serving as starting materialin the reaction according to the present invention. The production of all these products is described in detail in Examples 1 to 11d of U.S. Patent. Number 2,952,682.

The process according to the present invention which avoids one step in the multiple-step synthesis of reserpine and related compounds considerably facilitates isolation of the reaction products. Furthermore, the use of the expensive and dangerous diazomethane which is subject to vigorous decomposition and the handling of which is quite burdensome is also: avoided. An additional advantage of the present process isthe fact that not only the methyl ester but also other esters of the levor otatory 3B acetoxy 2a methoxy 7 0x0 l,2,3,4,4aa,7,8, 83.0: octahydronaphthalene 1 3 carboxylic acid of Formula I may be produced in a simple way.

The favorable results achieved by the method according to the present invention are quite surprising and could not be foreseen in view of the fact that usually hydroxy acid compounds of this type of compounds are readily lactonized in the presence of acetic acid anhydride and that ordinarily very poor results are achieved when esterifying the levorotatory 3B-acetoxy-2a-methoxy-7-oxol,2,3,4,4ao,7,8,8aa-octahydronaphthalene-lfl carboxylic acid of Formula Ia by using as esterifying agents alkyl esters of sulfurous acid or alcohols in the presence of an acid or even dimethyl sulfate in the presence of a strong base, for instance, "sodium hydroxide or potassium hydroxide. f

The following examples serve to illustrate the present invention without, however, limiting the' same thereto.

More particularly, the respective alkyl sulfates, solvents, or alkali metals jused and the reaction temperature may be varied in accordance with the principles set forth herein and in the'claims annexed heret o. i

The melting points given in the examples are points of instantaneous rneltingdetermined onthe'Maquenne block.

The racemic mixtures of the described optically active compounds may also be used as starting materials in the process according to the present invention although there is no advantage in proceeding in such a manner.

EXAMPLE 1 Preparation of the Levorotatory 3 8-Acet0xy-2a-Meth0xy- 7-Ox0-I,2,3,4,4am,7,8,82r& O'ctahya'ronaphthalene-Ifi- Carboxylic Acid (Formula Ia) METHOD A.-ACET YLATION OF THE ACID 0E FORMULA III p I V 5 g. of the levorotatory 3 p-hydroxy-hanethoxyJ-oxo- 1,2,3,4,4aa,7,8,8aa octahydronaphthalenerl,B-carboxylic acid of Formula 'I'II which'isprepared' according to US. Patent Number.2,952,682 and which has a melting point of 197 C. and a specific rotatory power of [a] 9='170 (concentration: 0.5% in ethanol), are. added with mechanical stirring to 10 cc. of absolutely dry pyridine while the reaction mixture is kept in a nitrogen atmosphere. 7.5 cc. of acetic acid anhydride. are added. The solid compound which is at first suspended in the solvent dissolves rapidly. The solution is, allowedto stand overnight while stirring and continuing introduction of nitro-' gen. The solution is then cooled to 05 Cr 5 cc. of water and thereafter 15 cc. of a saturated solution of sodium chloride which has 1 been cooled. to about +5 C. are added. The resultingmixture islacidifie'd with stirringto a pH-value of 2.0.by gradual 'addition of 2 N hydrochloric acid. The levorotatory' '3p acetoxy-2amethoxy-7-oxo-1,2,3,4,4ad,7,8,tlao -octahydronaphthalenelfi-carboxyliciacid (Formula Ia) precipitates soon in the form of crystals. They are filtered with suction, washed with water, and dried. Said. compound is sufiicientlypure for the esterification reaction according .to the following Examples 2 and 3. It is slightly soluble'in water, dilute aqueous acids, ether, benzene, and ethyl acetate, soluble in ethanol, methanol, and ing point is 227;C..

After recrystallization from methanol for analysis, its melting point is 228-229 C. and its, specific rotatory power is [a] =2'11;" ethanol).

Analysis.+C H O =282.28.. Calculated: 59.56% C; 6.43% H; 34.01% 0. Found: 59.6% C; 6.5% H; 34.0%O..

Acid number: Calculated: 198.5. Found: 198.2. Saponification number: Calculated: 397. Found:

Its ultraviolet absorption spectrum in ethanol shows a maximum'at 226 III/1. with an intensity of absorption 15:400. 0

This compound has the literature. a

dimethyl form amide. Its meltnot been described heretofore in (concentration: 0.5% in METHOD B.ACETYLATION OF THE ZINC SALT OF THE ACID OF, FORMULA III 1250 g. of zinc powder are added to a mixture of 9 l. of acetone and l l. of acetic acid which has previously been cooled to about +5 C. After cooling to about C. with good mechanical stirring and while passing nitrogen through the reaction vessel, 1 kg. of the levorotatory lactone of oa-bromo 8 3 hydroxy-2amethoxy-3j3,5fiepoxy 7 oxo 4aa,8aa decahydronaphthalene-lB-carboxylic acid (Formula II) are added. Although the re action mixture is cooled by means of a freezing mixture of ice and salt, its temperature rises to 1820 C. Stirring is continued until the temperature has dropped to about 3 C. Excess zinc powder is filtered off and washed with acetone. The combined filtrate and washing liquors are evaporated to dryness in a vacuum. Small amounts of acetic acid which are retained by and adhere to the solid residue, are carried away by acetone which is "added once or twice to the residue and is again distilled olf. The resulting zinc salt of the levorotatory 3 5-hydroxy-2amethoxy-7-oxo-1,2,3,4,4aa,7,8,8au-ootahydronaphthalene- IjS-oarboxylic acid is mixed with l l. of pyridine and dissolved by heating at 80 C. with stirring, while the reaction mixture is kept in a streaming nitrogen atmosphere. After dissolution of said zinc salt, 1 l. of acetic acid anhydri-de is added while keeping the temperature of the reaction mixture at about 20 C. The reaction mixture is allowed to stand at room temperature until the next morning. While cooling externally, the solution is rendered Congo acid by the addition of dilute sulfuric acid. Thereafter, the solution is cooled to 0 C. The precipitated levorotatory 35-acetoxy-2a-methoxy-7-oxo-1,2,3, 4,4aa,7,8,8aa ootahydronaphthalene-lB-carboxylic acid (Formula la) is filtered with suction and washed with water until the wash waters do not yield a precipitate on adding a barium chloride solution. Adhering water is removed by suction and the crystals are dried. The resulting acid is identical with that described in Example 1A.

EXAMPLE 2 Preparation 0] the Levorotatory Methyl Ester of 3B- Acet0xy-2a-Meth0xy-7-Ox0-1,2,3,4,4au,7,8,8aa ctahydronaphthalene-lfl-Carbaxylic Acid (Formula lb) In a 20 1. reaction vessel equipped with a mechanical stirrer and a thermometer, 1 kg. of the levorotatory 3/3- acetoxy-2a-methoxy-7-oxo-1,2,3,4,4aa,7,8,8aa octahydronaphthalene-lfi-carboxylic acid prepared according to Example 1a or lb is mixed with 4 l. of acetone. A solution of 320 g. of sodium bicarbonate in 4 l. of water is added thereto in small portions with stirring. After the addition is completed, a homogeneous reaction mixture is obtained. 340 cc. of dimethyl sulfate are added all at once and stirring is continued at 20-25 C. for 3 hours. In the same manner as before, without discontinuing stirring, a solution of 80 g. of sodium bicarbonate in l l. of water and thereafter 80 cc. of dimethyl sulfate are added. Stirring is continued at 20-25 C. for 3 hours. The same procedure is repeated with the same amounts of reagents, but the time of additional stirring is reduced to minutes. Thereafter, the reaction mixture is allowed to stand until the next morning. The solution is extracted several times by means of methylene chloride. The combined extracts are washed first with a saturated sodium bicarbonate solution and then with water. They are dried over anhydrous magnesium sulfate. After filtration and purification by means of charcoal, the solution is evaporated to dryness in a vacuum. Methylene chloride which is retained by the solid residue is removed by addition of and distillation with isopropyl ether. The remaining crystals are purified by recrystallization from isopropyl ether which dissolves the compound on 'boiling. After cooling, the crystals are filtered with suction and Washed several times with cold isopropyl ether. A first crop of 900 g. (86% of the theoretical amount) of the levorotatory methyl ester of 3fl-acetoxy-Zm-methoxy-7-oxo- 1,2,3,4,4az,7,8,8aa-octahydronaphthalene lfl-carboxylic acid (Formula 112) are obtained. The mother liquors are concentrated to a small volume and are allowed to stand in the ice-box for crystallization. The precipitated crystals are filtered with suction and triturated with a small amount of isopropyl ether. The solvent is completely removed by suction and the crystals are dried. This second crop weighs 60 g. to g. which corresponds to 67% of the theoretical yield, thus rendering the total yield of the process t0-92-93% ofthe theoretical amount. The resulting compound melts at 96 C. and has a specific rotatory power of [a] =-201i2 (concentration: 0.5% in ethanol). It is identical with the methyl ester compound described in the US. Patent Number.

2,952,682. It is very slightly soluble in water and dilute aqueous acids, soluble in alcohol, ether, acetone, benzene,

and chloroform.

EXAMPLE 3 Preparation of the Lejvorotalory Ethyl Ester 0f 33- The preparation of said compound is carried out in the same manner as described in Example 2. 10 g. of the levorotatory 3fi-acetoxy-2a-methoxy-7-oxo-1,2,3,4,4aa,7,

8,8aa-octahydronaphthalene-lfl-carboxylic acid are suspended in 80 cc. of acetone. A solution of 6.4 g. of sodium bicarbonate in 80 cc. of ,distilled water is added thereto. After. the addition of 9 cc. of diethylsulfate, 20 cc. of acetone are admixed in order to avoid'separation of the reaction mixture into two layers. The solution is allowed to stand at room temperature for 48 hours thereby stirring the mixture from time to time. The solution is extracted several times by means of methylene chloride. The combined organic extracts are washed first with distilled water, then with a saturated sodium bicarbonate solution, and finally with water. They are dried and evaporated to dryness. treated with isopropyl ether as described in Example 2. A first crop of 7.35 g. (67% of the theoretical amount) of the levorotatory ethyl ester of 3fl-acetoxy-2a-methoxy- 1,2,3,4,4au,7,8,8aa-octahydronaphthalene-1B carboxylic acid (Formula Ib) is obtained. Said compound melts at 74 C. and has a specific rotatory power of [a] =-185 (concentration: 0.5 in ethanol). It is insoluble in water, slightly soluble in isopropyl ether, quite soluble in ether, soluble in methanol, ethanol, ethyl acetate, benzene, and methylene chloride, very soluble in chloroform.

Analysis. C H O =310.34. Calculated: 61.92% C; 7.15% H; 30.93% 0. Found: 61.8% C; 7.2% H; 31.1% 0.

The ultraviolet absorption spectrum in ethanol shows a maximum at 226m and an excitation coefficient a: 11,600.

This compound has not yet been described in the literature.

Conversion of the lower alkyl esters of the levorotatory 3,5-acetoxy-2a-methoxy-7-oxo-1,2,3,4,4aa,7,8,8aa-octahydronaphthalene-lfi-carboxylic acid of Formula Ib' obtained according to the present invention into reserpine proceeds in the same manner as described in US. Patent Number 2,952,682 by converting said esters into the levorotatory lfl-carb'oxy methyl-Zfi-alkoxy carbonyl-3am ethoxy-4 3-acetoxy-fifi-formyl cyclohexane by ozonizing the compound of Formula 1b inacetic acid ethyl ester or methylene chloride at temperatures between 0 C. and -60 C., reacting the resulting ozonide with zinc powder in the presence of acetic acid followed by oxidation by means of chromic acid .or periodic acid or directly by the action of water or of iodic acid or periodic acid on said ozonide. The methyl ester of the carboxy methyl cyclohexane compound, obtained by reaction with diazo- (Formula The residue is.

methane in amixture of methylene chloride and ether is then condensed with 6-methoxy tryptamine. The condehsation product yields, after a treatment with sodium borohydride and thereafter with alcoholic sodium hydrox-' ide solution, the 'dextrorotat'ory 'ISB-hydroxy-lLlh-dimethoxy-3-oxo 16/8" carboxy-2,3-seco 200: yohinrbane.

, This compound is lactonized to the corresponding lactone, by heating with acetic acid anhydride, acetic acid, and lithium acetate. 7 Reaction of said lactone with phosphorus oXychloride, while'heating, yields the lactone of 10 in this new reserpine synthesis is described in detail in ples 11g to k, 12, and 13 of said patent.

We claim:

The process of preparing the levorotatory in ethanol lower alkyl esters of 3B-acetoXy-Ze-methoxy-7-oxo-1,2,3, 4,4ad,-7,8,8aaoctahydronaphthalene lfi-carboxylic acid, wherein said lower alkyl is a member selected from U.S Patent Number 2,952,682 and especially in Examthe group consisting of methyl and ethyl which comprises th e steps of Y 7 (g1) subjecting a member selected from the group ,consisting .of the levorotatory in ethanol 3fi-hydroxynaphthalene-lfi carboxylic acid and its zinc salt to the action of acetic acid anhydride in the presence to a tertiary base selected from the group consisting of pyridine, methyl ethyl pyridine and triethylamine and precipitating the levorotatory in ethanol 3B-acetoXy-Zwmethoxy-7-oxoa1,2,3,4,4a,7,-8, 8au-octahydronaphthalene 1,6- carboxylic acid by aciditying the reaction mixture;

(b) converting said carboxylic acid into its alkali metal salts;

(c) subjecting said alkali metal salt in a homogeneous medium in a mixture of water and a neutral hydroxyl group-free organic solvent to the action of a di-(1ower alkyl) sulfate selected from the group consisting of dimethyl sulfate and diethyl sulfate and (d) recovering said levorotatory in ethanol lower alkyl ester of 3,B-acetoxy-ZwrnethoxyJ-oxo-l,2,3,4, 4aa,7,8,8aa octahydronaphthalene 1/3 carboxylic acid.

References Cited in the file of thispatent V UNITED STATES PATENTS Woodward Apr. 21, 1959 OTHER REFERENCES Woodward et a1.: J. Am. Chem. Soc., 78, 2023-5 30 (1956).

Migrdichian: Organic Synthesis, vol. I, p.327, Reinhold, 1957. n 

